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New Scientist Live

Rabies may not be the invincible killer we thought

By Ferris Jabr

Earlier this month, 8-year-old Precious Reynolds of California became only the sixth person known to survive rabies without receiving a vaccine shortly after infection. At the University of California Davis Children’s Hospital doctors treated Reynolds with the Milwaukee protocol – an experimental procedure that plunges the patient into a drug-induced coma, taking the brain “offline” while the immune system scours the virus from infected neurons.

But the Milwaukee protocol is not a miracle cure for rabies – far from it. Since Rodney Willoughby of the Children’s Hospital of Wisconsin in Milwaukee developed the treatment in 2004, the protocol has been tried at least 35 times around the world in attempts to save people with rabies. Including Reynolds, only five have ostensibly benefited from the treatment.

Why has the Milwaukee protocol worked in only a few cases? The answer may be that the survivors owe their lives not to the experimental treatment, but to a combination of fortunate circumstances and a robust response from their own immune systems.

New research suggests that rabies is not quite the unequivocally fatal disease we think it is. The six known survivors may have been infected with weak strains of the rabies virus that their immune systems were able to eventually scrub from their brains – with or without the Milwaukee protocol.

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Beware bats

On 12 September 2004, 15-year-old Jeanna Giese scooped up a bat from the floor of St Patrick’s Church in her hometown of Fond du Lac, Wisconsin. As she left the church, the bat bit her finger. Thirty-seven days later, Giese entered St Agnes Hospital in Fon du Lac with a fever, double vision and a twitchy arm. When her mother mentioned the bat to the doctors they diagnosed Giese with rabies and referred her to Willoughby.

If someone receives a series of vaccines within a few days of being bitten by a rabid animal they almost always survive rabies. But once the virus has spent a few weeks travelling through the peripheral nervous system to the brain – and serious symptoms like paralysis, insomnia and foaming at the mouth appear – death soon follows.

Determined to treat Giese, Willoughby searched the research literature and noticed that autopsies of people with rabies showed no signs of brain damage. This, he reasoned, meant the virus was not exploding nerve cells – it was subtly interfering with neurochemical communication, disrupting how the brainstem regulates heart rate and breathing. If he could use drugs like ketamine and midazolam to induce a coma – muffling the brain so it evades the chemical curse of the rabies virus – he might be able to buy the immune system enough time to clear the infection. It worked. Giese recovered, although she still has some slight speech and motor problems.

Weak vaccine

On 6 March 2009, a 17-year-old girl entered a community hospital in Texas with a severe headache, rash and weakness in the limbs. Her doctors diagnosed her with encephalitis and administered antiviral and antibacterial drugs. When the girl mentioned contact with bats two months earlier during a hiking trip, the doctors tested her for rabies and found antibodies against the virus in her blood. They gave her single doses of rabies vaccine and human rabies immune globulin (HRIG) instead of the full dose, fearing she might develop too strong an immune response and damage her brain. Even without intensive care and the Milwaukee protocol, the girl recovered swiftly and was discharged.

The recent case of Precious Reynolds shares important characteristics with the 2004 and 2009 incidents. Firstly, none of the three girls was infected by a dog – Reynolds was most likely bitten or scratched by a feral cat. Different animals host different strains of the virus and the dog virus has always been the most fatal to humans worldwide. Secondly, none of the girls tested positive for the virus itself, only for antibodies to it, which suggests their immune systems had already mounted a defence and cleared most of what was likely a weaker strain of the virus.

In all three cases it is possible that the human immune system – with or without the Milwaukee protocol – vanquished a weak strain of the rabies virus. Researchers have known for years that some animals in the wild and in the lab survive rabies all on their own. New research points to the blood-brain barrier as “the arbiter of life and death” in a case of rabies, as D. Craig Hooper at Thomas Jefferson University in Philadelphia, Pennsylvania, puts it.

Hooper and his colleague Bernhard Dietzschold have pioneered research on how the blood-brain barrier permits immune cells to attack the rabies virus in the brains of mice. “The dogma has always been that when the rabies virus reaches the brain there is no hope for recovery,” says Dietzschold. “We have shown in animal models that this is not right – the immune system can clear the virus from the central nervous system.”

Cloaked viruses

Hooper and Dietzschold have discovered that the immune system responds quite differently to virulent and weaker strains of the rabies virus. The virulent strains are more cunning, effectively cloaking themselves from the immune system until it is too late. But weaker strains give themselves away to the immune system more quickly – perhaps because they have more glycoproteins, tiny surface molecules to which antibodies bind. If the immune system detects a weak rabies virus early enough, it grants immune B and T cells access to the brain.

When Hooper and Dietzschold gave mice that already had rabies a weakened but live form of the rabies virus, they found that the mice cleared the infection on their own. All current rabies vaccines for people – both preventative and post-infection – use tiny bits of dead virus that do not clear viruses from the central nervous system, says Hooper. A weakened live version of the rabies virus could be a future alternative to the Milwaukee protocol for people who do not realise they have rabies until it’s almost too late.

The work also rewrites the story of rabies as an unbeatable killer. “Are there people out there who have had rabies and recovered without signs at all?” wonders Hooper. “We look at rabies as a lethal disease when it appears there are exceptions.”